Timing of whole genome duplication is associated with tumor-specific MHC-II depletion in serous ovarian cancer

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting.


Statistics
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For survival analysis, the pwr.anova.test()function from the pwr R package (v1.3-0) was used to determine sample size.For the remainder of analyses, no sample size calculations were conducted, and sample size was pragmatic.
No samples were excluded from the bulk RNA sequencing One sample was excluded from single nuclei RNA sequencing as sufficient nuclei could not be extracted Analyses were performed on finite patient samples, and for much of the study, existing data, hence analyses were not replicated.
No randomisation was undertaken.
The pathologist who scored HLA DR + DP + DQ antibody staining had no information on the WGD status of patients.Otherwise, no blinding was performed.

Plants
Describe the methods by which all novel plant genotypes were produced.This includes those generated by transgenic approaches, gene editing, chemical/radiation-based mutagenesis and hybridization.For transgenic lines, describe the transformation method, the number of independent lines analyzed and the generation upon which experiments were performed.For gene-edited lines, describe the editor used, the endogenous sequence targeted for editing, the targeting guide RNA sequence (if applicable) and how the editor was applied.was applied.was applied.
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Cancer Study Group used a confidential Microsoft Access database for data collection.The 10x Chromium platform was used to to generate single nuclei RNAseq (snRNAseq) libraries using the 10x Genomics single cells 33 `reagent kit v3.1.Libraries were sequenced on on the Illumina NovaSeq6000 (paired end 150bp reads, 40,000 reads per cell).Single nuclei RNA sequencing was aligned to to the reference genome GRCh38 using CellRanger.All post-processing analyses were conducted in in Rstudio v4.1.0.WGS and bulk RNAseq analyses#

Materials
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Not applicable -not a clinical trialNot applicable -not a clinical trial Ambispective collection of data from clinical notes from individuals who had high grade serous ovarian cancer and had consented to participation in the Australian Ovarian Cancer Study.Not applicable -not a clinical trial nature portfolio | reporting summary